SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma.

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.

Unveiling the distinctive ossification patterns of diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis using computed tomography three-dimensional reconstruction.

OBJECTIVE: To quantitatively analyze the morphological characteristics of osteophytes in DISH and syndesmophytes in AS, and summarize different ossification patterns to help identify the two diseases. Associated factors for new bone formation would be investigated. METHODS: Fifty patients with DISH and 50 age-, sex-, CT examination site- matched patients with AS were enrolled. Radiographic and clinical data were reviewed. Osteophytes (syndesmophytes) in front of each vertebral body and the corresponding intervertebral disc space were defined as vertebral osteophytes unit (VOU). The volume, angle and location (contralateral, ipsilateral, bilateral) of osteophytes in each VOU were measured and compared between DISH and AS groups. RESULTS: In each VOU, the volume and angle of osteophytes in DISH were significantly larger. The best osteophytes volume and angle cutoff value in predicting DISH was 0.59 cm3 and 40.15°. Contralateral, bilateral, ipsilateral osteophytes were recorded in 59.32%, 36.38%, 4.3% of assessed VOUs in patients with DISH and 64.78%, 29.31%, 5.91% in AS (p<0.001), respectively. As to ipsilateral osteophytes, the volume was inversely correlated with the center of the vertebral body to the center of the descending aorta (DISH: r = -0.45, p= 0.01; AS: r = -0.83, p<0.001). Advanced age, disease duration, smoking and overweight contribute to the progression of osteophytes and syndesmophytes. CONCLUSION: Morphological features of osteophytes are helpful to distinguish DISH with AS. Aortic pulsations inhibit or hinder new bone formation in both DISH and AS. Maintaining normal BMI could postpone osteophytes formation.

Development and validation of ferroptosis-related lncRNA signature and immune-related gene signature for predicting the prognosis of cutaneous melanoma patients.

Ferroptosis, a form of cell death caused by iron-dependent peroxidation of lipids, plays an important role in cancer. Recent studies have shown that long noncoding RNAs (lncRNAs) are involved in the regulation of ferroptosis in tumor cells and are also closely related to tumor immunity. Immune cell infiltration in the tumor microenvironment affects the prognosis and clinical outcome of immunotherapy in melanoma patients, and immune cell classification may be able to accurately predict the prognosis of melanoma patients. However, the prognostic value of ferroptosis-related lncRNAs (FRLs) in melanoma has not been thoroughly explored, and it is difficult to define the immune characteristics of melanoma. We used The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) database, and the FerrDb database to identify FRLs. FRLs with prognostic value were evaluated in an experimental cohort utilizing univariate, LASSO (least absolute shrinkage and selection operator) and multivariate Cox regression, followed by in vitro assays evaluating the expression levels and the biological functions of three candidate FRLs. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to assess the validity of the risk model, and the drug sensitivity of FRLs was examined by drug sensitivity analysis. The differentially expressed genes between the high- and low-risk groups in the risk model were enriched in the immune pathway, and we further found immune gene signatures (IRGs) that could predict the prognosis of melanoma patients through a series of methods including single-sample Gene Set Enrichment Analysis (ssGSEA). Finally, two GEO cohorts were used to validate the predictive accuracy and reliability of these two signature models. Our findings suggest that FRLs and IRGs have the potential to predict the prognosis of patients with cutaneous melanoma.

Urchin-Shaped Au-Ag@Pt Sensor Integrated Lateral Flow Immunoassay for Multimodal Detection and Specific Discrimination of Clinical Multiple Bacterial Infections.

A new lateral flow immunoassay strip (LFIA) combining sensitive detection and identification of multiple bacteria remains a huge challenge. In this study, we first developed multifunctional urchin-shaped Au-Ag@Pt nanoparticles (UAA@P NPs) with a unique combination of colorimetric-SERS-photothermal-catalytic (CM/SERS/PT/CL) properties and integrated them with LFIA for multiplexed detection and specific discrimination of pathogenic bacteria in blood samples. Unlike the conventional LFIA that relied on antibody (Ab), this novel LFIA introduced 4-mercaptophenylboronic acid (4-MPBA) as an ideal Ab replacer that was functionalized on UAA@P NPs (UAA@P/M NPs) with outstanding binding and enrichment capacities toward bacteria. Taking Staphylococcus aureus (S. aureus) as model bacteria, the limit of detection (LOD) was 3 CFU/mL for SERS-LFIA, 27 CFU/mL for PT-LFIA, and 18 CFU/mL for CL-LFIA, three of which were over 330-fold, 37-fold, and 55-fold more sensitive than ordinary visual CM-LFIA, respectively. Besides, this SERS-LFIA is capable of identifying three types of bacterial spiked blood samples (E. coli, S. aureus, and P. aeruginosa) effectively according to specific bacterial Raman "fingerprints" by partial least-squares-discriminant analysis (PLS-DA). More importantly, this LFIA was successfully applied to blood samples with satisfactory recoveries from 90.3% to 108.8% and capable of identifying the infected patients (N = 4) from healthy subjects (N = 2) with great accuracy. Overall, the multimodal LFIA incorporates bacteria discrimination and quantitative detection, offering an avenue for early warning and diagnosis of bacterial infection.

Well-Ordered Au Nanoarray for Sensitive and Reproducible Detection of Hepatocellular Carcinoma-Associated miRNA via CHA-Assisted SERS/Fluorescence Dual-Mode Sensing.

Ultra-sensitive detection of cancer-related biomarkers in serum is of great significance for early diagnosis, treatment, prognosis, and staging of cancer. In this work, we proposed a surface-enhanced Raman scattering and fluorescence (SERS/FL) dual-mode biosensor for hepatocellular carcinoma (HCC)-related miRNA (miR-224) detection using the composition of well-arranged Au nanoarrays (Au NAs) substrate coupled with the target-catalyzed hairpin assembly (CHA) strategy. The hot spots densely and uniformly distributed on the Au array offers considerably enhanced and reproducible SERS signals, along with their wide and open surface to facilitate miR-224 adsorption. By this sensing strategy, the target miR-224 can be detected in a wide linear range (1 fM to 1 nM) with a limit of detection of 0.34 fM in the SERS mode and 0.39 fM in the FL mode. Meanwhile, this biosensor with exceptional specificity and anti-interference ability can discriminate target miR-224 from other interference miRNAs. Practical analysis of human blood samples also demonstrated considerable reliability and repeatability of our developed strategy. Furthermore, this biosensor can distinguish HCC cancer subjects from normal ones and monitor HCC patients before and after hepatectomy as well as guide the distinct Barcelona clinic liver cancer (BCLC) stages. Overall, benefiting from a well-arranged Au nanoarray, CHA amplification strategy, and SERS/metal enhanced fluorescence effect, this established biosensor opens new avenues for the early prediction, warning, monitoring, and staging of HCC.

Penile terra firma-forme dermatosis in children.

Terra firma-forme dermatosis (TFFD) is a rare, acquired keratinization disorder that predominantly affects children and young adults. Herein, we report three unusual cases of penile TFFD in children and the histopathologic and ultrastructural observations.

A cell phone app for facial acne severity assessment.

Acne vulgaris, the most common skin disease, can cause substantial economic and psychological impacts to the people it affects, and its accurate grading plays a crucial role in the treatment of patients. In this paper, we firstly proposed an acne grading criterion that considers lesion classifications and a metric for producing accurate severity ratings. Due to similar appearance of acne lesions with comparable severities and difficult-to-count lesions, severity assessment is a challenging task. We cropped facial skin images of several lesion patches and then addressed the acne lesion with a lightweight acne regular network (Acne-RegNet). Acne-RegNet was built by using a median filter and histogram equalization to improve image quality, a channel attention mechanism to boost the representational power of network, a region-based focal loss to handle classification imbalances and a model pruning and feature-based knowledge distillation to reduce model size. After the application of Acne-RegNet, the severity score is calculated, and the acne grading is further optimized by the metadata of the patients. The entire acne assessment procedure was deployed to a mobile device, and a phone app was designed. Compared with state-of-the-art lightweight models, the proposed Acne-RegNet significantly improves the accuracy of lesion classifications. The acne app demonstrated promising results in severity assessments (accuracy: 94.56%) and showed a dermatologist-level diagnosis on the internal clinical dataset.The proposed acne app could be a useful adjunct to assess acne severity in clinical practice and it enables anyone with a smartphone to immediately assess acne, anywhere and anytime.

Analysis on tumor immune microenvironment and construction of a prognosis model for immune-related skin cutaneous melanoma. / å ç–«ç›¸å ³çš„çš®è‚¤é»‘è‰²ç´ ç˜¤é¢„åŽæ¨¡åž‹æž„å»ºåŠè‚¿ç˜¤å ç–«å¾®çŽ¯å¢ƒåˆ†æž.

OBJECTIVES: Malignant melanoma is a highly malignant and heterogeneous skin cancer. Although immunotherapy has improved survival rates, the inhibitory effect of tumor microenvironment has weakened its efficacy. To improve survival and treatment strategies, we need to develop immune-related prognostic models. Based on the analysis of the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Sequence Read Archive (SRA) database, this study aims to establish an immune-related prognosis prediction model, and to evaluate the tumor immune microenvironment by risk score to guide immunotherapy. METHODS: Skin cutaneous melanoma (SKCM) transcriptome sequencing data and corresponding clinical information were obtained from the TCGA database, differentially expressed genes were analyzed, and prognostic models were developed using univariate Cox regression, the LASSO method, and stepwise regression. Differentially expressed genes in prognostic models confirmed by real-time reverse transcription PCR (real-time RT-PCR) and Western blotting. Survival analysis was performed by using the Kaplan-Meier method, and the effect of the model was evaluated by time-dependent receiver operating characteristic curve as well as multivariate Cox regression, and the prognostic model was validated by 2 GEO melanoma datasets. Furthermore, correlations between risk score and immune cell infiltration, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) score, immune checkpoint mRNA expression levels, tumor immune cycle, or tumor immune micro-environmental pathways were analyzed. Finally, we performed association analysis for risk score and the efficacy of immunotherapy. RESULTS: We identified 4 genes that were differentially expressed in TCGA-SKCM datasets, which were mainly associated with the tumor immune microenvironment. A prognostic model was also established based on 4 genes. Among 4 genes, the mRNA and protein levels of killer cell lectin like receptor D1 (KLRD1), leukemia inhibitory factor (LIF), and cellular retinoic acid binding protein 2 (CRABP2) genes in melanoma tissues differed significantly from those in normal skin (all P<0.01). The prognostic model was a good predictor of prognosis for patients with SKCM. The patients with high-risk scores had significantly shorter overall survival than those with low-risk scores, and consistent results were achieved in the training cohort and multiple validation cohorts (P<0.001). The risk score was strongly associated with immune cell infiltration, ESTIMATE score, immune checkpoint mRNA expression levels, tumor immune cycle, and tumor immune microenvironmental pathways (P<0.001). The correlation analysis showed that patients with the high-risk scores were in an inhibitory immune microenvironment based on the prognostic model (P<0.01). CONCLUSIONS: The immune-related SKCM prognostic model constructed in this study can effectively predict the prognosis of SKCM patients. Considering its close correlation to the tumor immune microenvironment, the model has some reference value for clinical immunotherapy of SKCM.

Novel chloroquine derivative suppresses melanoma cell growth by DNA damage through increasing ROS levels.

Melanoma is a fatal cancer with a significant feature of resistance to traditional chemotherapeutic drugs and radiotherapy. A mutation in the kinase BRAF is observed in more than 66% of metastatic melanoma cases. Therefore, there is an urgent need to develop new BRAF-mutant melanoma inhibitors. High-dose chloroquine has been reported to have antitumour effects, but it often induces dose-limiting toxicity. In this study, a series of chloroquine derivatives were synthesized, and lj-2-66 had the best activity and was selected for further investigation. Furthermore, the anti-BRAF-mutant melanoma effect and mechanism of this compound were explored. CCK-8 and colony formation assays indicated that lj-2-66 significantly inhibited the proliferation of BRAF-mutant melanoma cells. Flow cytometry revealed that lj-2-66 induced G2/M arrest in melanoma cells and promoted apoptosis. Furthermore, lj-2-66 increased the level of ROS in melanoma cells and induced DNA damage. Interestingly, lj-2-66 also played a similar role in BRAF inhibitor-resistant melanoma cells. In summary, we found a novel chloroquine derivative, lj-2-66, that increased the level of ROS in melanoma cells and induced DNA damage, thus leading to G2/M arrest and apoptosis. These findings indicated that lj-2-66 may become a potential therapeutic drug for melanoma harbouring BRAF mutations.

Lachnospira is a signature of antihistamine efficacy in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a mast cell-driven disease with many advances in its aetiology and pathogenesis over the past years. The main treatment of CSU is oral second-generation antihistamines. However, only an average of 50% of CSU patients responded adequately to conventional or quadruple doses of non-sedative antihistamines. Meanwhile, gut microbiota can affect the efficacy of drugs. The purpose of this study was to investigate the relationship between gut microbiota and the efficacy of antihistamines in patients with CSU. The patients with CSU were divided into responders and non-responders according to the efficacy of antihistamine monotherapy. The gut microbiota of faecal samples from 15 responders and 15 non-responders was detected by 16S rDNA sequencing, and the differential bacterial species between the two groups were verified by quantitative polymerase chain reaction (qPCR). Additional faecal samples from 30 responders and 30 non-responders were used as an extended cohort to further verify the above differential bacterial species by qPCR. Lachnospiraceae and its subordinate taxa were found to be the main differences in gut microbiota between responders and non-responders. The abundance of Lachnospira in responders was higher than that in non-responders. Lachnospira exhibits moderate diagnostic value in evaluating the efficacy of antihistamine. Lachnospira is a signature for predicting the efficacy of antihistamine in patients with CSU.

Clinical manifestations and outcome of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody positive patients with interstitial lung disease.

OBJECTIVES: To analyse the clinical features and risk factors of acute/subacute interstitial pneumonia (A/SIP) and death in patients with positive anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) and positive anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab). METHODS: Interstitial lung disease (ILD) patients with anti-ARS+ or anti-MDA5+ were recruited. Their demographics, clinical manifestations, laboratory data were collected and they were followed up for 1 year. Risk factors of A/SIP and mortality were analysed. RESULTS: 71 patients with anti-ARS+ ILD and 31 patients with anti-MDA5+ ILD were included. Incidence of ulcerative rash, Gottron's sign, pulmonary infection and A/SIP in the anti-MDA5+ group were significantly higher than those in the anti-ARS+ group, Creatine kinase (CK), leukocyte count, and lymphocyte count were lower, the value of serum ferritin (SF) was higher, and 12-month cumulative survival rate was lower. Advanced age, anti-MDA5+ and low immunoglobulin G (IgG) level were independent predictors of A/SIP. The decreased PaO2 and elevated SF were independent predictors for poor prognosis in A/SIP patients. CONCLUSIONS: Compared to anti-ARS+ group, the anti-MDA5+ group was more prone to ulcerative rash, Gottron's sign and pulmonary infection. Patients with anti-MDA5+, advanced age and decreased values of IgG were more likely to have A/SIP, while patients with A/SIP had lower incidence of myositis and arthritis. Mortality of A/SIP patients increased with higher serum ferritin level.

Value of contrast-enhanced ultrasonography in assessing the activity of idiopathic retroperitoneal fibrosis: a prospective study.

OBJECTIVES: We aimed to evaluate changes in the contrast-enhanced ultrasound (CEUS) parameters in patients with idiopathic retroperitoneal fibrosis (RPF) before and after treatment, and to analyse the value of CEUS to assess RPF activity. METHODS: We performed a prospective study that included patients with idiopathic RPF who were treated for RPF at our hospital from April 2016 to April 2019. All patients underwent CEUS examination and some of them underwent positron emission tomography/computed tomography (PET/CT) examination simultaneously. CEUS parameters included tube wall and peripheral thickness, arterial wall intensity, and lumen intensity. The changes in CEUS parameters before and after treatment were evaluated, and their correlations with the standardised uptake value (SUVmax), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed. RESULTS: Thirty-one active idiopathic RPF patients were enrolled, of whom 11 underwent PET/CT examination before treatment. Tube wall and peripheral thickness (r=0.743, p<0.01) and arterial wall intensity (r=0.702, p<0.05) both correlated significantly with SUVmax. Lumen intensity did not correlate significantly with SUVmax (r=0.544, p=0.084). The correlation coefficients between lesion thickness and ESR levels were 0.508 (p=0.037), between lesion thickness and CRP levels were 0.575 (p=0.016). Arterial wall intensity and lumen intensity were not significantly correlated with ESR or CPR levels. Tube wall and peripheral thickness, arterial wall intensity, decreased significantly after treatment (p=0.001), while the lumen intensity was not significantly changed after treatment. CONCLUSIONS: Our findings suggest that CEUS, a radiation-free and repeatable detection method, is effective for assessing idiopathic RPF disease activity.

Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization.

Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.

Adherence, Efficacy, and Safety of Wearable Technology-Assisted Combined Home-Based Exercise in Chinese Patients With Ankylosing Spondylitis: Randomized Pilot Controlled Clinical Trial.

BACKGROUND: Clinical practice guidelines recommend that exercise is essential in the self-management of ankylosing spondylitis (AS). Attending supervised interventions requiring periodic medical center visits can be difficult and patients may decline participation, whereas effective home-based exercise interventions that do not require regular medical center visits are likely to be more accessible for AS patients. OBJECTIVE: The goal of the research was to investigate the adherence, efficacy, and safety of a wearable technology-assisted combined home-based exercise program in AS. METHODS: This was a 16-week investigator-initiated, assessor-blinded, randomized, pilot controlled trial conducted at Chinese People's Liberation Army General Hospital. We enrolled patients with AS who had no regular exercise habits and had been stable in drug treatment for the preceding month. Patients were randomly assigned (1:1) using a computer algorithm. An exercise program consisting of moderate-intensity aerobic exercise and functional exercise was given to the patients in the intervention group. The exercise intensity was controlled by a Mio FUSE Heart Rate Monitor wristband, which uses photoplethysmography to measure heart rate. Patients in the control group received usual care. The primary outcome was the difference in the Ankylosing Spondylitis Disease Activity Score (ASDAS). The secondary outcomes were patient global assessment (PGA), physician global assessment (PhGA), total pain, nocturnal pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BAS Functional Index (BASFI), BAS Metrology Index (BASMI), Spondyloarthritis International Society Health Index (ASAS HI), 36-item Short Form Survey (SF-36), maximal oxygen uptake (VO2) max, body composition, range of motion of joints, and muscle endurance tests. Retention rate, adherence rate, barriers to being active, and adverse events were also assessed. RESULTS: A total of 77 patients were screened, of whom 55 (71%) patients were enrolled; 2% (1/55) withdrew without treatment after randomization. Patients were assigned to the intervention (n=26) or control group (n=28). The median adherence rate of the prescribed exercise protocol was 84.2% (IQR 48.7%-97.9%). For the primary outcome, between-group difference of ASDAS was significant, favoring the intervention (-0.2, 95% CI -0.4 to 0.02, P=.03). For the secondary outcomes, significant between-group differences at 16 weeks were detected in PGA, PhGA, total pain, BASDAI, BASDAI-fatigue, BASDAI-spinal pain, BASDAI-morning stiffness intensity, BASFI, and BASMI. Moreover, the frequency of difficulty in ASAS HI-motivation at 16 weeks was less in the intervention group (P=.03). Between-group difference for change from baseline were also detected in VO2 max, SF-36, back extensor endurance test, and the range of motion of cervical lateral flexion at 16 weeks. Lack of time, energy, and willpower were the most distinct barriers to being active. Incidences of adverse events were similar between groups (P=.11). CONCLUSIONS: Our pilot study suggests that this technology-assisted combined home-based exercise program can improve the clinical outcomes of patients with AS who have no exercise habit, with good adherence and safety profile. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900024244; http://www.chictr.org.cn/showproj.aspx?proj=40176.

Identification of gut microbiota signatures in symptomatic dermographism.

Symptomatic dermographism (SD) is a recurrent inflammatory skin disease related to immunity; however, the details remain elusive. In view of the important role of gut microbiota in immune regulation, the purpose of this study is to investigate the alterations of gut microbiota in SD and explore the potential bacterial biomarkers for diagnosis. A case-control study including SD patients and normal controls (NCs) was carried out. Gut microbiota of the participants was analysed by the 16S rDNA sequencing of faecal samples. The linear discriminant analysis effect size and the receiver operating characteristic curve (ROC) analysis were used to identify the bacterial biomarkers. Forty-four participants were included in this study. The alpha-diversity and beta-diversity of gut microbiota differed significantly between SD patients and NCs. The abundance of Verrucomicrobia, Ruminococcaceae and their subordinate taxa were reduced in SD patients, while Enterobacteriales and its subordinate taxon exhibited higher relative abundance compared with NCs. Subdoligranulum and Ruminococcus bromii showed a potential diagnostic value for SD, and Prevotella stercorea was negatively relevant to duration of SD. Furthermore, the pyruvate, butyric acid and histamine metabolism pathway were likely to be involved in the pathogenesis of SD. Our results revealed that the gut microbiota of SD patients experienced obvious changes, and Verrucomicrobia, Ruminococcaceae and Enterobacteriales were microbiota signatures for SD.

Symptoms of systemic lupus erythematosus are diagnosed in leptin transgenic pigs.

Leptin is a well-known adipokine that plays a critical role in immune responses. To further explore the immunological roles of leptin, we developed a transgenic leptin pig controlled by the pig leptin (pleptin) promoter to overexpress leptin. Symptoms typically associated with systemic lupus erythematosus (SLE) were evident in this transgenic pig strain, including anemia, leukopenia, and thrombocytopenia as well as kidney and liver impairment. Histologically, there were increased immunoglobulin G (IgG) levels, elevated antiplatelet antibody (APA) levels, and deposition of immune complexes in the kidney and liver. In addition, anti-double-stranded DNA antibodies (dsDNAs), antinuclear antibodies (ANAs), and antinucleosome antibodies (ANuAs) were all significantly increased in serum immunological examinations. These findings were also accompanied by repression of the regulatory T cell (Treg) ratio. Significantly, glucocorticoid experimental therapies partially relieved the autoimmune responses and bleeding symptoms observed in these transgenic leptin pigs. Together, these results indicate that leptin plays a critical role in the development of autoimmune disorders and demonstrate that our transgenic leptin pigs can act as a valuable model of SLE.

Optimal potassium management strategy to enhance crop yield and soil potassium fertility under paddy-upland rotation.

BACKGROUND: An unbalanced application of potassium (K) fertilizer usually destabilizes crop yield and affects soil K fertility. Developing a sustainable K management strategy requires improvements in crop yield without reducing soil K supply capacity over the long term. A combination of field experiments of K fertilization and straw return using rice (Oryza sativa L.)-oilseed rape (Brassica napus L.) rotation was designed to develop an optimal K management strategy. RESULTS: The results showed the best strategy to maintain yield was KG +S (input equivalent K removed by seed treatment and straw return), KS +KG (input equivalent K removed by straw and seed) and KC +S (conventional K fertilization and straw return) treatments, and the yield gap among different treatments expanded with the extension of planting years. There were significant differences present in rice and rape K uptake, although no differences in seed K uptake were observed under different K management strategies. The K balance was approximately maintained under KG +S and KS +KG treatments, and negative K balances were present for KN (no K application), KC (conventional fertilization), +S (straw return) and KS treatments (input equivalent K that removed by straw treatment). A positive balance was observed under KC +S treatment. Slight changes in soil exchangeable and nonexchangeable K were observed under KG +S and +S treatments. However, high inputs of K fertilizer prevented the improvement of agronomic efficiency and recovery efficiency of K. CONCLUSIONS: In summary, the optimal K management strategy was KG +S, which stabilizes the crop yield, maintains soil K fertility and maximizes K use efficiency. © 2020 Society of Chemical Industry.

Nutrition-mediated cell and tissue-level anatomy triggers the covariation of leaf photosynthesis and leaf mass per area.

Plants in nutrient-poor habitats converge towards lower rates of leaf net CO2 assimilation (Aarea); however, they display variability in leaf mass investment per area (LMA). How a plant optimizes its leaf internal carbon investment may have knock-on effects on structural traits and, in turn, affect leaf carbon fixation. Quantitative models were applied to evaluate the structural causes of variations in LMA and their relevance to Aarea in rapeseed (Brassica napus) based on their responses to nitrogen (N), phosphorus (P), potassium (K), and boron (B) deficiencies. Leaf carbon fixation decreased in response to nutrient deficiency, but the photosynthetic limitations varied greatly depending on the deficient nutrient. In comparison with Aarea, the LMA exhibited diverse responses, being increased under P or B deficiency, decreased under K deficiency, and unaffected under N deficiency. These variations were due to changes in cell- and tissue-level carbon investments between cell dry mass density (N or K deficiency) and cellular anatomy, including cell dimension and number (P deficiency), or both (B deficiency). However, there was a conserved pattern independent of nutrient-specific limitations-low nutrient availability reduced leaf carbon fixation but increased carbon investment in non-photosynthetic structures, resulting in larger but fewer mesophyll cells with a thicker cell wall but a lower chloroplast surface area appressed to the intercellular airspace, which reduced the mesophyll conductance and feedback-limited Aarea. Our results provide insight into the importance of mineral nutrients in balancing the leaf carbon economy by coordinating leaf carbon assimilation and internal distribution.

The relationship between TRAF6 and tumors.

Tumor necrosis factor receptor (TNFR)-related factors (TRAFs) are important linker molecules in the tumor necrosis factor superfamily (TNFSF) and the Toll-like/interleukin-1 receptor (TLR/ILR) superfamily. There are seven members: TRAF1-TRAF7, among those members, tumor necrosis factor receptor-associated factor 6 (TRAF6) is upregulated in various tumors, which has been related to tumorigenesis and development. With the in-depth study of the relationship between TRAF6 and different types of tumors, TRAF6 has oncogenic characteristics involved in tumorigenesis, tumor development, invasion, and metastasis through various signaling pathways, therefore, targeting TRAF6 has provided a novel strategy for tumor treatment. This review summarizes and analyzes the role of TRAF6 in tumorigenesis and tumor development in combination with the current research on TRAF6 and tumors.

A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products.

BACKGROUND: Melanoma is one of the most aggressive tumors with the remarkable characteristic of resistance to traditional chemotherapy and radiotherapy. Although targeted therapy and immunotherapy benefit advanced melanoma patient treatment, BRAFi (BRAF inhibitor) resistance and the lower response rates or severe side effects of immunotherapy have been observed, therefore, it is necessary to develop novel inhibitors for melanoma treatment. METHODS: We detected the cell proliferation of lj-1-59 in different melanoma cells by CCK 8 and colony formation assay. To further explore the mechanisms of lj-1-59 in melanoma, we performed RNA sequencing to discover the pathway of differential gene enrichment. Western blot and Q-RT-PCR were confirmed to study the function of lj-1-59 in melanoma. RESULTS: We found that lj-1-59 inhibits melanoma cell proliferation in vitro and in vivo, induces cell cycle arrest at the G2/M phase and promotes apoptosis in melanoma cell lines. Furthermore, RNA-Seq was performed to study alterations in gene expression profiles after treatment with lj-1-59 in melanoma cells, revealing that this compound regulates various pathways, such as DNA replication, P53, apoptosis and the cell cycle. Additionally, we validated the effect of lj-1-59 on key gene expression alterations by Q-RT-PCR. Our findings showed that lj-1-59 significantly increases ROS (reactive oxygen species) products, leading to DNA toxicity in melanoma cell lines. Moreover, lj-1-59 increases ROS levels in BRAFi -resistant melanoma cells, leading to DNA damage, which caused G2/M phase arrest and apoptosis. CONCLUSIONS: Taken together, we found that lj-1-59 treatment inhibits melanoma cell growth by inducing apoptosis and DNA damage through increased ROS levels, suggesting that this compound is a potential therapeutic drug for melanoma treatment.